Association between Degree of Anaplasia and Degree of Inflammation with the Expression of COX-2 in Feline Injection Site Sarcomas.

Feline injection site sarcomas (FISSs) are mesenchymal neoplasms that develop at the sites of delivery of vaccines or other injectable products. Vaccine adjuvants can trigger an intense and persistent inflammatory response that may lead to neoplastic transformation. The proinflammatory role of cyclo-oxygenase (COX)-2 is well known and its overexpression has prognostic value in multiple neoplastic processes. One hundred and seventeen FISSs were evaluated for the degree of inflammation and anaplasia. Immunohistochemistry was used to determine the expression of COX-2 in these sarcomas. There was a significant association between the degree of inflammation and the expression of COX-2 by neoplastic cells. COX-2 expression was lower in tumours with higher degrees of anaplasia. These findings may be useful in predicting the sensitivity of FISSs to treatment with COX-2 inhibitors. The potential therapeutic use of such agents could then be restricted to tumours with lower degrees of anaplasia.

Uveodermatological syndrome (Vogt-Koyanagi-Harada-like syndrome) with generalized depigmentation in a Dachshund.

A 3-year-old, female, black and tan Dachshund was referred with visual impairment, bilateral anterior and posterior uveitis, poliosis, and generalized dermal depigmentation. Complete blood counts and biochemical parameters, including T3 and T4, were normal. The skin biopsy showed lichenoid dermatoses with dermal infiltration of histiocytes and lymphocytes suggesting uveodermatological syndrome. Medical treatment was initiated with oral prednisone and azathioprine, and topical prednisolone and atropine. The clinical signs improved, vision was retained, and the skin began to repigment 2 months following the initiation of therapy.

Pulmonary function in relation to cigarette smoking and smoking cessation. MRFIT Research Group.

BACKGROUND: More than half of the subjects in the MRFIT smoked at baseline and 10% of the subjects stopped smoking permanently during the first year of the trial. In this report, rates of decline in forced expiratory volume in 1 sec (FEV1) are compared for early permanent quitters and smokers who continued to smoke throughout the trial. METHODS: Since pulmonary function testing was not standardized across all centers until the third annual visit cycle, change in FEV1 is examined over the latter half of the trial; the level of FEV1 is analyzed cross-sectionally at the midpoint of the trial. Analyses are limited to 4,926 subjects who never used beta-blockers or smoked cigars, cigarillos, or pipes during the trial and who had annual FEV1s measured over 2-4 years in the latter half of the trial. RESULTS: Quitters during the first 12 months experienced smaller declines in FEV1 over the latter half of the trial than continuing smokers, with -50.7 ml/year versus -59.0 ml/year, respectively, adjusted for the level of FEV1 (P = 0.05). Cross-sectionally, those who had never smoked, former smokers, quitters, and continuing smokers showed a gradient of decreasing FEV1, and all four smoking groups were significantly different from each other (P less than 0.05). CONCLUSIONS: These data suggest that if a middle-aged, healthy smoker stopped smoking permanently, he could expect his FEV1 to deteriorate at a more gradual rate 3-4 years after stopping smoking than a similar smoker who continued to smoke. No information was available for the complete MRFIT cohort on the pulmonary function effects immediately following smoking cessation.

An examination of the efficiency of some quality assurance methods commonly employed in clinical trials.

The cost and efficiency of training clinical centre staff and of duplicate data entry in clinical trials is reviewed. Training is an essential component of quality assurance programmes and it is usually carried out at regular intervals in long-term clinical trials. Initial training of staff and regular retraining is important to assure standardization and it can lead to reduced trial costs. Interim training for new staff and for remedial purposes is less efficient than regularly scheduled training sessions. Regional centres for training and the use of computer aided instruction are two ways such interim training can be made more efficient and standardized. Duplicate data entry or verification can result in a substantial reduction in data entry errors depending on the nature of the data being keyed. Selective verification should especially be considered for important fields for which consistency checks cannot be performed, that are alphabetic or that are several characters in length. Quality assurance procedures should be implemented to monitor data entry accuracy in clinical trials.

Quality control aspects of blood pressure measurements in the Multiple Risk Factor Intervention Trial.

Quality control of an ongoing study of blood pressure must be an active, dynamic process in which attempts are continually made to reduce error and bias and maintain comparability among clinics. Training is an important means of initiating and maintaining proper procedures. In addition, changes in procedures during the trial must be properly evaluated so that their impact upon the conduct of the trial is known and, if necessary, quantifiable. The monitoring of quality measurement of blood pressure in a large clinical trial such as MRFIT must be a two-pronged effort that considers observation and evaluation of methods of measuring blood pressure in actual clinical practice and evaluation of data resulting from these procedures.

Quality control in the MRFIT local screening and clinic laboratory.

Quality control was emphasized in the screening and clinic laboratory during the early stages of the trial to cover all aspects of screening, and in the later stages to cover local testing used to monitor the participant in the clinic and to guarantee collection of valid specimens to be shipped to the Central Laboratory. Special attention throughout the trial was focused on techniques for collection of specimens, since it was recognized that analytical results could not be better than the quality of the specimens. Training courses, on-site visits, and newsletters were used to sensitize the staff of the clinic laboratory about the necessity to follow protocol. Any monitoring evidence of carelessness, use of deteriorated supplies, failure to follow safety rules, and deviation from directions in the MRFIT Manual of Operations resulted in memoranda from the Coordinating Center or the Central Laboratory.

Quality control of biochemical data in the Multiple Risk Factor Intervention Trial: Central Laboratory.

The acquisition of quality biochemical data in the MRFIT was enhanced by writing detailed protocols, instituting strict rules for collecting and shipping specimens, setting high goals for analytical performance, using reliable means to transfer data, employing dedicated and competent analysts, and having a director of the Central Laboratory who believed in and enforced an effective quality control system. A Laboratory Quality Control Subcommittee was formed to work with this director in solving laboratory problems, with the Coordinating Center in conducting appropriate monitoring, with the Quality Control Committee in documenting the quality of data and investigating any laboratory problems, and with other committees of the directors and Program Office in responding to any questions raised about laboratory aspects of the trial. All of these efforts culminated in reliable biochemical data.

Quality control aspects of pulmonary function testing in the Multiple Risk Factor Intervention Trial.

Pulmonary function testing was used in MRFIT to monitor the presence of airways disease and to assess changes in pulmonary function over time. The pulmonary function indices that were measured were FEV1, FVC, and MMEF, (FEF25-75). Quality control of technician training, equipment maintenance, data collection, and data measurement were essential to ensure that results, over time and from various clinics, could be compared. Based on the MRFIT experience, it is strongly recommended that centralized training in testing techniques and spirometer maintenance take place before a clinical trial begins, and periodically throughout a trial. Such training, combined with quality control follow-up, should prevent the loss of data due to inadequate spirometer maintenance and invalid testing procedures.

Forms control and error detection procedures used at the Coordinating Center of the Multiple Risk Factor Intervention Trial (MRFIT).

Although methods used for data collection and quality assurance for large-scale clinical trials are important to critical reading of trial results and have been published, such reporting is the exception rather than the rule. In the MRFIT, systematic methods for processing large volumes of data over a long period of time were developed. The methods were designed to detect and control a variety of errors and to leave a complete audit trial of the processing of forms and corrections to forms. Many of these methods evolved and were refined during the course of the study as a result of trial and error. If one were to start over, the methods described herein would be modified. The field of data processing is evolving, and it is important for statistical and data processing staff of coordinating centers to recognize this and continually evaluate and update their methods. For example, the simultaneous entry and computer editing of forms is becoming more feasible with time. Also, more sophisticated intelligent data entry equipment is available for central use. Near the end of MRFIT, some data received at the Coordinating Center were entered and edited on a minicomputer. The parameter-driven edits described previously were performed at the time of data entry. Additional modifications to the content of the data dictionary for future studies are also being considered. The incorporation into the data dictionary of consistency checks (both deterministic and probabilistic) between fields on different forms would facilitate the specification of complex edit checks and would provide better documentation of the edit checks actually performed. Incorporating definitions of the numeric codes for each field would improve the documentation and facilitate reporting using statistical packages. Dedicated computer hardware should also be a major consideration of coordinating centers in future clinical trials. For MRFIT, a dedicated system was used from 1978 to the end of the trial. With the continued decline in hardware costs, dedicated systems can and should be considered, even for trials much smaller than MRFIT. We believe the system developed for processing data in the MRFIT has several advantages. It satisfies the requirements identified by Karrison or a system of data editing and control, it is largely self-documenting as a result of the data dictionary approach taken, and it is easily adaptable to other clinical studies.

Quality control in the Multiple Risk Factor Intervention Trial Nutrition Modality.

One of the principal objectives of the MRFIT was to teach and motivate participants assigned to the SI group to adhere to a fat-controlled dietary regimen over the course of the trial. The magnitude of the trial (with more than 12,000 participants, half of them assigned to the SI protocol, to be followed for at least 6 years in 22 separate centers) presented new challenges for maintenance of quality control over a nutrition intervention program. Collection of data to monitor changes in dietary intake over time in SI and UC groups, as well as information to assess dietary adherence levels in SI participants also presented large-scale challenges in maintenance of quality control. The MRFIT formulated many of its initial nutrition intervention and data collection decisions based on experience of the earlier National Diet Heart Study (NDHS). In order to avoid coding 7-day dietary records by local clinic nutritionists (as in NDHS), the trial opted for collection of 24-hour dietary recalls that were coded centrally at the Nutrition Coding Center. It necessitated extra attention to training and certification of clinic nutritionist-interviewers to be certain that NCC coders had sufficiently precise information about all foods entered on dietary recall forms. Since dietary intake data were collected over a time span of approximately 10 years, procedures for updating the food composition database and coding rules were a necessity. Continuing attention to training and monitoring of performance of clinic nutritionist-interviewers also was important. The MRFIT nutrition intervention program was designed with the need for interclinic comparability of intervention techniques in mind. This required not only development of study-wide nutrition intervention materials, but also necessitated ongoing attention to staff training and monitoring procedures in order to ensure intercenter comparability of efforts. The success of the nutrition intervention modality depended upon the continuing efforts of the nutrition counselors not only to achieve dietary adherence but also to monitor levels of dietary adherence over time. The NDHS experience served as a springboard for designing the MRFIT nutrition intervention and data collection procedures. It is hoped that techniques for maintaining and monitoring quality control over the MRFIT nutrition modality as outlined in this chapter may prove useful to future planners.

A long-term nutrition intervention experience: lipid responses and dietary adherence patterns in the Multiple Risk Factor Intervention Trial.

Nutrition counselors in the Multiple Risk Factor Intervention Trial (MRFIT) were able to help middle-aged men who were at high risk for coronary heart disease change their dietary habits, maintain those changes over time, and decrease their serum cholesterol levels. Most of a 7.5% mean serum cholesterol reduction achieved after 6 years of nutrition intervention occurred during the first year of the trial and was thereafter sustained. Total cholesterol and low-density lipoprotein cholesterol fraction decreases indicated improvement in terms of coronary heart disease risk. The food record rating, a numerical, semi-objective adherence technique that assesses a 3-day food record with respect to lipid-lowering potential, was used throughout the trial to measure adherence to recommended food patterns. Participants with lower food record rating scores, which indicate better adherence, demonstrated greater reductions in serum total cholesterol, plasma total cholesterol, and low-density lipoprotein fraction cholesterol determinations on a group basis. Subjective evaluations of the suitability of home and working environments, evidence of deviation from the MRFIT food patterns, and overall nutrition program motivation also showed that as ratings in each category became more favorable, lower food record rating scores and greater blood lipid reductions were consistently observed. The subgroup of participants who were non-smokers and not hypertensive demonstrated greater lipid responses and better dietary adherence. Continued smoking and antihypertensive medications appeared to adversely influence dietary adherence and/or lipid reductions. The MRFIT experience, however, demonstrated for the first time that dietary changes and blood lipid reductions can be achieved after the initial intervention effect, despite a continued emphasis on high blood pressure management and smoking cessation.